{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:02:59Z","timestamp":1792598579146,"version":"4.5.0"},"reference-count":162,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T00:00:00Z","timestamp":1699056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"A.G Leventis Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR\u2019s genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR\u2019s multifaceted role in human reproduction and its clinical implications for reproductive disorders.<\/jats:p>","DOI":"10.3390\/ijms242115965","type":"journal-article","created":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T14:51:01Z","timestamp":1699109461000},"page":"15965","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Gonadotropin-Releasing Hormone Receptor (GnRHR) and Hypogonadotropic Hypogonadism"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4590-4778","authenticated-orcid":false,"given":"Pavlos","family":"Fanis","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6890-8395","authenticated-orcid":false,"given":"Vassos","family":"Neocleous","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0023-1860","authenticated-orcid":false,"given":"Irene","family":"Papapetrou","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Nicosia, Nicosia 1678, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas A.","family":"Phylactou","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicos","family":"Skordis","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Nicosia, Nicosia 1678, Cyprus"},{"name":"Division of Paediatric Endocrinology, Paedi Center for Specialized Paediatrics, Nicosia 2024, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/humupd\/dmv059","article-title":"GnRH and GnRH receptors in the pathophysiology of the human female reproductive system","volume":"22","author":"Maggi","year":"2016","journal-title":"Hum. 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